Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.

The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases

Role of IL-17A in murine models of COPD airway disease.

peer reviewedSmall airway fibrosis is a major pathological feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Chronic inflammatory cells accumulate around small airways in COPD and are thought to play a major role in small airway fibrosis. Mice deficient in alpha/beta T cells have recently been shown to be protected from both experimental airway inflammation and fibrosis. In these models, CD4+Th17 cells and secretion of IL-17A are increased. However, a pathogenic role for IL-17 in specifically mediating fibrosis around airways has not been demonstrated. Here a role for IL-17A in airway fibrosis was demonstrated using mice deficient in the IL-17 receptor A (il17ra) Il17ra-deficient mice were protected from both airway inflammation and fibrosis in two different models of airway fibrosis that employ COPD-relevant stimuli. In these models, CD4+ Th17 are a major source of IL-17A with other expressing cell types including gammadelta T cells, type 3 innate lymphoid cells, polymorphonuclear cells, and CD8+ T cells. Antibody neutralization of IL-17RA or IL-17A confirmed that IL-17A was the relevant pathogenic IL-17 isoform and IL-17RA was the relevant receptor in airway inflammation and fibrosis. These results demonstrate that the IL-17A/IL-17 RA axis is crucial to murine airway fibrosis. These findings suggest that IL-17 might be targeted to prevent the progression of airway fibrosis in COPD

Vegetative Ecological Characteristics of Restored Reed (Phragmites australis) Wetlands in the Yellow River Delta, China

In this study, we compared ecological characteristics of wetland vegetation in a series of restoration projects that were carried out in the wetlands of Yellow River Delta. The investigated characteristics include plant composition structure, species diversity and community similarity in three kinds of Phragmites australis wetlands, i.e. restored P. australis wetlands (R1, R2, R3 and R4: restored in 2002, 2005, 2007 and 2009, respectively), natural P. australis wetland (N) and degraded P. australis wetland (D) to assess the process of wetlands restoration. The coverage of the R1 was 99%, which was similar to natural wetland. Among all studied wetlands, the highest and lowest stem density was observed in R1 and R2, respectively, Plant height and stem diameter show the same trend as N > R2 > R1 > R3 > D > R4. Species diversity of restored P. australis wetlands became closed to natural wetland. Both species richness and Shannon–Wiener index had similar tendency: increased first and then decreased with restored time. The highest species richness and species diversity were observed in R2, while the lowest values of those parameters were found in natural P. australis wetland. Similarity indexes between restored wetlands and natural wetland increased with the restoration time, but they were still less than 50%. The results indicate that the vegetation of P. australis wetlands has experienced a great improvement after several years’ restoration, and it is feasible to restored degraded P. australis wetlands by pouring fresh water into those wetlands in the Yellow River Delta. However, it is notable that costal degraded P. australis wetland in this region may take years to decades to reach the status of natural wetland

Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways

There is an unmet need in severe asthma where approximately 40% of patients exhibit poor β-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca2+-activated Cl− channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ∼580,000 compounds. The anthelmintics niclosamide, nitazoxanide, and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting β-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the β-agonist isoproterenol showed only partial effects. Thus, antagonists of TMEM16A and repositioning of niclosamide and nitazoxanide represent an important additional treatment for patients with severe asthma and COPD that is poorly controlled with existing therapies. It is of note that drug repurposing has also attracted wide interest in niclosamide and nitazoxanide as a new treatment for cancer and infectious disease. For the first time we identify TMEM16A as a molecular target for these drugs and thus provide fresh insights into their mechanism for the treatment of these disorders in addition to respiratory disease

Variation in transpiration and its relationship with growth for Pinus ponderosa Lawson in southern Arizona.

The climate, water loss, arid certain aspects of growth in semiarid-site ponderosa pine were measured from 1 February 1966 to 10 March 1967 to determine the environmental relationships governing transpiration, internal water balance, and tracheid production. Water loss from branches and from entire trees was measured by means of polyethylene enclosures. Changes In internal water status of the tree were ascertained from seasonal trends in loss of water from branches and diurnal as well as seasonal changes in the radius of the bole. The elongation of branches and needles, and the production of tracheids and their size and wall thickness were related to the coincident internal water status of the tree. The branch enclosure technique was found to be a convenient method by which the water loss process could be studied. The seasonal changes in transpiration undoubtedly were influenced by the elevated temperatures that developed within the enclosure during the day. However, the elevated temperatures did not appear to adversely influence branch and needle elongation within the chamber. Warm air temperatures and low soil moisture during June and early July increased internal water stress, reduced daytime water loss, and reduced elongation of branches and needles. Fewer tracheids were produced in the upper bole. They were small and had thick walls, Moisture from rains in July replenished soil moisture and larger, thin-walled tracheids were differentiated so that the intra-anntjlar band of small, thick-walled cells became apparent. Gradual shrinkage of the upper bole in June implied that the above changes in growth were due to changes in internal water deficits. There were no marked changes in tracheid sizes and wall thickness in the lower bole during 1966. Intra-annular bands of narrow, thick-walled tracheids occurred times during the last 10 years in the upper bole in the last 50 years in the lower bole. Graphical analysis showed that midday reductions in rates of xi transpiration during periods of low soil moisture and high air temperatures occurred in spite of steepening water vapor gradients and before stomates were closed. This evidence supports the hypothesis that reductions in water loss during midday may result directly from internal water deficits. Soil moisture, air temperature, and incident radiation appeared to influence transpiration by altering the availability of water, the vapor pressure gradient, and the energy available for evaporation.hydrology collectio

Decision-Making For Prairie Wetland Restorations

Assessments of wetland restorations in the prairie region are not done routinely and no accepted assessment framework exists. Wetland assessment protocols in the U.s. have varied over time from those emphasizing social significance to those attempting to quantify functions of wetlands from hydrogeomorphic considerations. A conceptual framework for restoration decision-making is presented that is based on optimizing wetland restoration success at both the landscape and site scales. This framework uses societal concerns, knowledge of factors that limit ecosystem recovery, and data on losses of different types of wetlands locally and regionally to establish restoration goals and guide site selection. These goals in turn generate restoration expectations or targets. Currently, restoration expectations are usually formulated only at the basin scale. Prairie pothole wetlands, however, were historically part of wetland complexes. Consequently, restoration efforts should focus on restoring complexes not isolated wetlands. Wetland restoration decision-making thus requires that landscape-level restoration expectations be part of all prairie pothole restorations. Landscape-level expectations should also be used in the assessment of these projects. Reference wetlands or historic data from the wetland and wetland complexes to. be restored are used to develop these restoration expectations

The effects of depth on periphytic growth in Douglas Lake.

In this study we investigated the relationship between light and periphytic communities in a freshwater lake. We sampled periphytic algae at increasing depths along a vertical transect in Douglas Lake. We anticipated that certain algal genera would reveal a preference for certain depths, that algal population sizes would decrease with increasing depth and that there would be fewer genera exploiting the lower depths.http://deepblue.lib.umich.edu/bitstream/2027.42/54337/1/2773.pdfDescription of 2773.pdf : Access restricted to on-site users at the U-M Biological Station

Establishment of Native Sedge Vegetation in Created Wetlands

This report presents the results of a four-year study on techniques for revegetation of native sedges in created basins. Although often the dominant genus in shallow wetlands, sedges (Carex spp.) do not readily recolonize after restoration or creation of the water table. It is unlikely that sedges will naturally establish in created wetlands. The results of seed germination studies on five Carex species suggest the highest germination rates in fresh seeds - with one exception. Wet/cold storage also can prolong seed viability for at least two-and-a-half years. Dry storage is not recommended for wetland sedge seeds. Short-term wet/cold treatment after prolonged dry storage does not improve germination rates. Sensitive to deep water, rising water levels, and competition during the establishment year, seedlings grew well across a wide range of water depths in subsequent growing seasons. Both species outcompeted annual weeds within two to three growing seasons, but not Phalaris arundinacea (reed canary grass). The study recommends weed control during the establishment year to prevent the invasion of P. arundinacea. Wetland soil promotes seedling growth relative to other soils, but does not affect germination rates. Because of the potential for the introduction of undesirable weeds, the study does not recommend the use of donor wetland soil. Instead, study results suggest the potential for the use of organic top-dressings.Minnesota Department of Transportatio

The Variability of Ring Characteristics within Trees as Shown by a Reanalysis of Four Ponderosa Pine

This item is part of the Tree-Ring Research (formerly Tree-Ring Bulletin) archive. It was digitized from a physical copy provided by the Laboratory of Tree-Ring research at The University of Arizona. For more information about this peer-reviewed scholarly journal, please email the Editor of Tree-Ring Research at [email protected]